Molecular Mechanisms Regulating Pancreatic Delta Cell Function and Dysfunction

调节胰腺 Delta 细胞功能和功能障碍的分子机制

基本信息

  • 批准号:
    10597228
  • 负责人:
  • 金额:
    $ 44.96万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary Islet glucose-stimulated somatostatin (Sst) secretion is lost in patients with type-2 diabetes (T2D) and in animal models of the disease, which contributes to disrupted glucagon and insulin secretion. It is generally accepted that Sst secretion from -cells occurs in response to elevated intracellular Ca2+, which primarily results from endoplasmic reticulum (ER) Ca2+ (Ca2+ER) release. However, the mechanisms that control -cell Ca2+ER handling and how they are altered in T2D are largely unknown. Data from our lab finds that the islet-enriched two-pore- domain K+ channel, TALK-1, is an ER localized channel in that provides a countercurrent for -cell Ca2+ER release and Ca2+ER leak. TALK-1-mediated augmentation of the electrochemical driving force for -cell Ca2+ER leak con- strains Ca2+ER storage, which limits glucose-stimulated Ca2+ER release and Sst secretion. Further data show that -cell Ca2+ER release and Sst secretion are amplified by glucose-induced allosteric activation of -cell Ca2+-sens- ing receptors (CaSRs). Finally, our preliminary data provide the first evidence that diabetic conditions diminish -cell Ca2+ER storage, which contributes to perturbations in glucose-stimulated Ca2+ handling and Sst secretion under diabetic conditions. Based on these exciting preliminary data, the overall objective of this proposal is to elucidate how -cell Ca2+ER is controlled and becomes disrupted during the pathogenesis of diabetes. This project will test the central hypothesis that glucose-stimulated -cell Sst secretion is amplified by CaSR-mediated Ca2+ER release, which is controlled by TALK-1 channel constraint of Ca2+ER storage. The rationale that underlies this project is that understanding how CaSR and TALK-1 control -cell Ca2+ER handling and Sst secretion will expose novel therapeutic targets for restoring glucose-stimulated Sst secretion and islet hormone secretion in T2D. This project will be accomplished with the following two specific aims: 1) Determine how -cell CaSR controls Ca2+ER handling, Sst secretion, and islet hormone secretion; and 2) Determine how TALK-1 channel control of Ca2+ER release modulates -cell function and dysfunction. Under the first aim, transgenic mice with -cell ablation of CaSR as well as human pseudoislets with ShRNA knockdown of -cell CaSR will be utilized to assess the roles of the Ca2+-sensing receptor during secretagogue modulation of -cell Ca2+ handling and Sst secretion. Aim1 will also determine how depletion of -cell Ca2+ER stores under diabetic conditions impacts CaSR signaling and Sst secretion. Under the second aim, the function TALK-1 channels on -cell Ca2+ER handling and function will be determined in mice with -cell specific ablation of TALK-1 and in human pseudoislets containing either -cells with knockdown of TALK-1 or expressing dominant negative TALK-1 channel subunits. Furthermore, Aim2 will determine how TALK-1 augmentation of -cell Ca2+ER depletion under the stressful conditions associated with diabetes contributes to -cell dysfunction. This project is significant because it is expected to illuminate mecha- nisms that alter -cell Ca2+ER handling and disrupt islet hormone secretion in T2D. Moreover, this project will identify pharmacological strategies for normalizing Sst secretion and reducing islet dysfunction in T2D.
项目摘要 在2型糖尿病(T2 D)患者和动物中,胰岛葡萄糖刺激的生长抑素(Sst)分泌丧失 该疾病的模型,这有助于破坏胰高血糖素和胰岛素分泌。人们普遍认为 Sst分泌从β-细胞发生在响应升高的细胞内Ca 2+,这主要是由于 内质网Ca ~(2+)释放。然而,控制胰岛细胞Ca 2 +ER处理的机制 以及它们在T2 D中是如何改变的,在很大程度上是未知的。我们实验室的数据发现,富含胰岛的两孔- 结构域K+通道(TALK-1)是一种ER定位的通道,为β细胞Ca ~(2+)ER释放提供逆流 Ca 2 +ER漏出。TALK-1介导的增强细胞Ca 2 +ER泄漏的电化学驱动力, 菌株Ca 2 +ER储存,限制葡萄糖刺激的Ca 2 +ER释放和Sst分泌。进一步的数据显示, 葡萄糖诱导的胰岛β细胞Ca 2 +-sens变构激活可增强胰岛β细胞Ca 2 +-ER释放和Sst分泌。 ing受体(CaSRs)。最后,我们的初步数据提供了第一个证据,表明糖尿病的条件减少, 胰岛细胞Ca 2 +ER储存,这有助于葡萄糖刺激的Ca 2+处理和Sst分泌的扰动 在糖尿病条件下。根据这些令人兴奋的初步数据,本提案的总体目标是 阐明在糖尿病发病过程中,β细胞Ca 2 +ER是如何被控制和被破坏的。这个项目 将检验葡萄糖刺激的β细胞Sst分泌被CaSR介导的Ca 2 +ER放大的中心假设 释放,这是由TALK-1通道限制的Ca 2 +ER存储控制。这背后的基本原理是 本项目的目的是了解CaSR和TALK-1如何控制胰岛细胞Ca 2 +ER的处理和Sst的分泌, 用于恢复T2 D中葡萄糖刺激的Sst分泌和胰岛激素分泌的新治疗靶点。这 本课题的主要目的是:1)确定细胞内CaSR对Ca ~(2+)ER的调控机制 处理、Sst分泌和胰岛激素分泌;以及2)确定TALK-1通道如何控制Ca 2 +ER 释放调节β-细胞功能和功能障碍。在第一个目标下,对转基因小鼠进行β细胞消融, 将利用CaSR以及具有β细胞CaSR的shRNA敲低的人假胰岛来评估CaSR的作用。 在促分泌素调节β细胞Ca ~(2+)处理和Sst分泌过程中,Ca ~(2+)敏感受体的作用。aim 1将 还确定了糖尿病条件下β细胞Ca 2 +ER储存的耗竭如何影响CaSR信号传导和Sst 分泌物。在第二个目标下,TALK-1通道在β细胞Ca 2 +ER处理和功能中的功能将是 在TALK-1的β细胞特异性消融的小鼠中和在含有β细胞的人假胰岛中测定 TALK-1敲低或表达显性负性TALK-1通道亚单位。此外,Aim 2将 确定TALK-1如何在应激条件下增强β细胞Ca 2 +ER耗竭, 糖尿病导致胰岛细胞功能障碍。该项目意义重大,因为它有望照亮机械- 在T2 D中改变胰岛细胞Ca 2 +ER处理和破坏胰岛激素分泌的细菌。此外,该项目将 鉴定用于使Sst分泌正常化和减少T2 D中胰岛功能障碍的药理学策略。

项目成果

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David Aaron Jacobson其他文献

David Aaron Jacobson的其他文献

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{{ truncateString('David Aaron Jacobson', 18)}}的其他基金

Secretagogue and Gi/o-GPCR signaling through the islet Na+/K+-ATPase in health and diabetes
健康和糖尿病中通过胰岛 Na /K -ATP 酶的促分泌素和 Gi/o-GPCR 信号传导
  • 批准号:
    10717045
  • 财政年份:
    2023
  • 资助金额:
    $ 44.96万
  • 项目类别:
Molecular Mechanisms Regulating Pancreatic Delta Cell Function and Dysfunction
调节胰腺 Delta 细胞功能和功能障碍的分子机制
  • 批准号:
    10443333
  • 财政年份:
    2022
  • 资助金额:
    $ 44.96万
  • 项目类别:
Molecular Mechanisms Regulating Pancreatic Delta Cell Function and Dysfunction
调节胰腺 Delta 细胞功能和功能障碍的分子机制
  • 批准号:
    10899152
  • 财政年份:
    2022
  • 资助金额:
    $ 44.96万
  • 项目类别:
Two-Pore-Domain Potassium Channels as Novel Targets for Modulating Islet Hormone Secretion
双孔域钾通道作为调节胰岛激素分泌的新靶点
  • 批准号:
    10408705
  • 财政年份:
    2019
  • 资助金额:
    $ 44.96万
  • 项目类别:
Two-Pore-Domain Potassium Channels as Novel Targets for Modulating Islet Hormone Secretion
双孔域钾通道作为调节胰岛激素分泌的新靶点
  • 批准号:
    9979836
  • 财政年份:
    2019
  • 资助金额:
    $ 44.96万
  • 项目类别:
2-Pore-Domain K+ Channels as Novel Targets for Modulating Islet Hormone Secretion
2 孔域 K 通道作为调节胰岛激素分泌的新靶点
  • 批准号:
    9044225
  • 财政年份:
    2013
  • 资助金额:
    $ 44.96万
  • 项目类别:
2-pore-domain K+ channels as novel targets for modulating islet hormone secretion
2孔域K通道作为调节胰岛激素分泌的新靶点
  • 批准号:
    9112994
  • 财政年份:
    2013
  • 资助金额:
    $ 44.96万
  • 项目类别:
2-pore-domain K+ channels as novel targets for modulating islet hormone secretion
2孔域K通道作为调节胰岛激素分泌的新靶点
  • 批准号:
    8690839
  • 财政年份:
    2013
  • 资助金额:
    $ 44.96万
  • 项目类别:
2-pore-domain K+ channels as novel targets for modulating islet hormone secretion
2孔域K通道作为调节胰岛激素分泌的新靶点
  • 批准号:
    8579232
  • 财政年份:
    2013
  • 资助金额:
    $ 44.96万
  • 项目类别:
Small molecule modulators of the two-pore-domain potassium channel, TREK-2
双孔域钾通道小分子调节剂 TREK-2
  • 批准号:
    8446273
  • 财政年份:
    2012
  • 资助金额:
    $ 44.96万
  • 项目类别:

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